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WO2008142110A1 - Moyens et méthode de diagnostic de l'insuffisance cardiaque chez un patient atteint d'une fibrillation atriale, à l'aide de gdf-15 et de peptides natriurétiques - Google Patents

Moyens et méthode de diagnostic de l'insuffisance cardiaque chez un patient atteint d'une fibrillation atriale, à l'aide de gdf-15 et de peptides natriurétiques Download PDF

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Publication number
WO2008142110A1
WO2008142110A1 PCT/EP2008/056261 EP2008056261W WO2008142110A1 WO 2008142110 A1 WO2008142110 A1 WO 2008142110A1 EP 2008056261 W EP2008056261 W EP 2008056261W WO 2008142110 A1 WO2008142110 A1 WO 2008142110A1
Authority
WO
WIPO (PCT)
Prior art keywords
amount
gdf
heart failure
peptide
atrial fibrillation
Prior art date
Application number
PCT/EP2008/056261
Other languages
English (en)
Inventor
Georg Hess
Andrea Horsch
Hendrik Hüdig
Dietmar Zdunkek
Original Assignee
Roche Diagnostics Gmbh
F. Hoffmann-La Roche Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Roche Diagnostics Gmbh, F. Hoffmann-La Roche Ag filed Critical Roche Diagnostics Gmbh
Priority to JP2010508842A priority Critical patent/JP5015318B2/ja
Publication of WO2008142110A1 publication Critical patent/WO2008142110A1/fr
Priority to US12/621,560 priority patent/US7955854B2/en

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/475—Assays involving growth factors
    • G01N2333/495—Transforming growth factor [TGF]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/58—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Brain natriuretic peptide [BNP, proBNP]; Cardionatrin; Cardiodilatin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/324—Coronary artery diseases, e.g. angina pectoris, myocardial infarction
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/325—Heart failure or cardiac arrest, e.g. cardiomyopathy, congestive heart failure

Definitions

  • Heart diseases are the leading cause of morbidity and mortality in the Western hemisphere. The said diseases can remain asymptomatic for long periods of time. However, they may have severe consequences once an acute cardiovascular event, such as myocardial infarction, as a cause of the cardiovascular disease occurs.
  • Heart failure is a condition that can result from any structural or functional cardiac disorder that impairs the ability of the heart to fill with or pump a sufficient amount of blood throughout the body. Even with the best therapy, heart failure is associated with an annual mortality of about 10%.
  • the present invention relates to a method of diagnosing heart failure in a subject exhibiting atrial fibrillation, said method comprising a) determining the amount of GDF- 15 in a sample of said subject; and b) comparing the amount of GDF- 15 determinant step a) with a suitable reference amount whereby heart failure is to be diagnosed.
  • Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99 %.
  • the p-values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001. More preferably, at least 60%, at least 70%, at least 80% or at least 90% of the subjects of a population can be properly identified by the method of the present invention.
  • subject as used herein relates to animals, preferably mammals, and, more preferably, humans.
  • the subject referred to in accordance with the aforementioned method suffers from heart failure or exhibits the symptoms or clinical parameters, such as an increased NT-proBNP level, accompanied therewith, i.e. being at least suspect to suffer from heart failure.
  • the subject referred to in accordance with the present invention shall also exhibit atrial fibrillation.
  • the pre-pro peptide (134 amino acids in the case of pre-proBNP) comprises a short signal peptide, which is enzymatically cleaved off to release the pro peptide (108 amino acids in the case of proBNP).
  • the pro peptide is further cleaved into an N-terminal pro peptide (NT -pro peptide, 76 amino acids in case of NT -proBNP) and the active hormone (32 amino acids in the case of BNP, 28 amino acids in the case of ANP).
  • Preferred natriuretic peptides according to the present invention are NT-proANP, ANP, NT -proBNP, BNP, and variants thereof.
  • natriuretic peptides are NT -proBNP or variants thereof.
  • heart failure relates to an impaired systolic and/or diastolic function of the heart.
  • heart failure referred to herein is also chronic heart failure.
  • Heart failure can be classified into a functional classification system according to the New York Heart Association (NYHA).
  • NYHA New York Heart Association
  • Patients of NYHA Class I have no obvious symptoms of cardiovascular disease but already have objective evidence of functional impairment.
  • Physical activity is not limited, and ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath).
  • Patients of NYHA class II have slight limitation of physical activity. They are comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea.
  • Patients of NYHA class III show a marked limitation of physical activity.
  • Heart failure i.e., an impaired systolic and/or diastolic function of the heart, can be determined also by, for example, echocardiography, angiography, szintigraphy, or magnetic resonance imaging. This functional impairment can be accompanied by symptoms of heart failure as outlined above (NYHA class II-IV), although some patients may present without significant symptoms (NYHA I).
  • heart failure is also apparent by a reduced left ventricular ejection fraction (LVEF). More preferably, heart failure as used herein is accompanied by a left ventricular ejection fraction (LVEF) of less than 60%, of 40% to 60% or of less than 40%.
  • GDF- 15 relates to a polypeptide being a member of the transforming growth factor (TGF)- ⁇ cytokine superfamily.
  • TGF transforming growth factor
  • GDF- 15 was originally cloned as macrophage-inhibitory cytokine- 1 and later also identified as placental transforming growth factor- ⁇ , placental bone morphogenetic protein, non-steroidal anti- inflammatory drug-activated gene-1, and prostate-derived factor (Bootcov loc cit; Hromas, 1997 Biochim Biophys Acta 1354:40-44; Lawton 1997, Gene 203:17-26; Yokoyama-Kobayashi 1997, J Biochem (Tokyo), 122:622-626; Paralkar 1998, J Biol Chem 273:13760-13767).
  • variants referred to above may be allelic variants or any other species specific homologs, paralogs, or orthologs.
  • variants referred to herein include fragments of the specific GDF- 15 polypeptides or the aforementioned types of variants as long as these fragments have the essential immunological and biological properties as referred to above. Such fragments may be, e.g., degradation products of the GDF- 15 polypeptides.
  • variants which differ due to posttranslational modifications such as phosphorylation or myristylation.
  • sample refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ.
  • Determining the amount of the peptides or polypeptides referred to in this specification relates to measuring the amount or concentration, preferably semi-quantitatively or quantitatively. Measuring can be done directly or indirectly.
  • Direct measuring relates to measuring the amount or concentration of the peptide or polypeptide based on a signal which is obtained from the peptide or polypeptide itself and the intensity of which directly correlates with the number of molecules of the peptide present in the sample.
  • a signal sometimes referred to herein as intensity signal -may be obtained, e.g., by measuring an intensity value of a specific physical or chemical property of the peptide or polypeptide.
  • Indirect measuring includes measuring of a signal obtained from a secondary component (i.e. a component not being the peptide or polypeptide itself) or a biological read out system, e.g., measurable cellular responses, ligands, labels, or enzymatic reaction products.
  • determining the amount of a peptide or polypeptide can be achieved by all known means for determining the amount of a peptide in a sample.
  • Said means comprise immunoassay devices and methods which may utilize labeled molecules in various sandwich, competition, or other assay formats.
  • Said assays will develop a signal which is indicative for the presence or absence of the peptide or polypeptide.
  • the signal strength can, preferably, be correlated directly or indirectly (e.g. reverse- proportional) to the amount of polypeptide present in a sample.
  • Further suitable methods comprise measuring a physical or chemical property specific for the peptide or polypeptide such as its precise molecular mass or NMR spectrum.
  • determining the amount of a peptide or polypeptide comprises the steps of (a) contacting a cell capable of eliciting a cellular response the intensity of which is indicative of the amount of the peptide or polypeptide with the said peptide or polypeptide for an adequate period of time, (b) measuring the cellular response.
  • the sample or processed sample is, preferably, added to a cell culture and an internal or external cellular response is measured.
  • the cellular response may include the measurable expression of a reporter gene or the secretion of a substance, e.g. a peptide, polypeptide, or a small molecule.
  • the expression or substance shall generate an intensity signal which correlates to the amount of the peptide or polypeptide.
  • determining the amount of a peptide or polypeptide comprises the step of measuring a specific intensity signal obtainable from the peptide or polypeptide in the sample.
  • a specific intensity signal may be the signal intensity observed at an m/z variable specific for the peptide or polypeptide observed in mass spectra or a NMR spectrum specific for the peptide or polypeptide.
  • an enzymatic reaction product may be measured (e.g. the amount of a protease can be measured by measuring the amount of cleaved substrate, e.g. on a Western Blot).
  • the ligand may exhibit enzymatic properties itself and the "ligand/peptide or polypeptide" complex or the ligand which was bound by the peptide or polypeptide, respectively, may be contacted with a suitable substrate allowing detection by the generation of an intensity signal.
  • the amount of substrate is saturating.
  • a suitable enzyme-substrate combination may result in a colored reaction product, fluorescence or chemoluminescence, which can be measured according to methods known in the art (e.g. using a light-sensitive film or a suitable camera system).
  • fluorescent labels include fluorescent proteins (such as GFP and its derivatives), Cy3, Cy5, Texas Red, Fluorescein, and the Alexa dyes (e.g. Alexa 568). Further fluorescent labels are available e.g. from Molecular Probes (Oregon). Also the use of quantum dots as fluorescent labels is contemplated.
  • Typical radioactive labels include 35 S, 125 I, 32 P, 33 P and the like.
  • a radioactive label can be detected by any method known and appropriate, e.g. a light-sensitive film or a phosphor imager.
  • Suitable measurement methods according the present invention also include precipitation (particularly immunoprecipitation), electrochemiluminescence (electro-generated chemiluminescence), RIA (radioimmunoassay), ELISA (enzyme- linked immunosorbent assay), sandwich enzyme immune tests, electrochemiluminescence sandwich immunoassays (ECLIA), dissociation-enhanced lanthanide fluoro immuno assay (DELFIA), scintillation proximity assay (SPA), turbidimetry, nephelometry, latex- enhanced turbidimetry or nephelometry, or solid phase immune tests.
  • precipitation particularly immunoprecipitation
  • electrochemiluminescence electrochemiluminescence (electro-generated chemiluminescence)
  • RIA radioimmunoassay
  • Suitable methods for fixing/immobilizing said ligand are well known and include, but are not limited to ionic, hydrophobic, covalent interactions and the like. It is also contemplated to use "suspension arrays" as arrays according to the present invention (Nolan 2002, Trends Biotechnol. 20(l):9-12).
  • the carrier e.g. a microbead or microsphere
  • the array consists of different microbeads or microspheres, possibly labeled, carrying different ligands.
  • Methods of producing such arrays for example based on solid-phase chemistry and photo-labile protective groups, are generally known (US 5,744,305).
  • the method of the present invention advantageously, allows for a reliable, fast and less cost intensive diagnosis and can be implemented even in portable assays, such as test stripes. Therefore, the method is particularly well suited for diagnosing emergency patients. Thanks to the findings of the present invention, a suitable therapy for a subject can be reliably selected, e.g., a therapy for heart failure. Severe side effects caused by the wrong treatment of patients can be avoided.
  • the present invention furthermore, relates to a device for diagnosing heart failure in a subject exhibiting atrial fibrillation comprising a) means for determining the amount of GDF- 15 in a sample of a subject exhibiting atrial fibrillation; and b) means for comparing the amount determined by the means of a) with a suitable reference amount whereby diagnosis of heart failure is allowed.
  • Said device may accordingly include an analyzing unit for the measurement of the amount of the peptides or polypeptides in an applied sample and a computer unit for processing the resulting data for the evaluation.
  • the means for comparison may comprise control stripes or tables allocating the determined amount to a reference amount.
  • the test stripes are, preferably, coupled to a ligand which specifically binds to the peptides or polypeptides referred to herein.
  • the strip or device preferably, comprises means for detection of the binding of said peptides or polypeptides to the said ligand. Preferred means for detection are disclosed in connection with embodiments relating to the method of the invention above.
  • Example 1 Determination of GDF- 15 and NT-proBNP in serum and plasma samples
  • a total of 273 patients having sinus rhythm when examined by electrocardiography were analyzed for changes in the GDF- 15 and NTproBNP levels. The same analysis was done for a total of 17 patients exhibiting atrial fibrillation. Moreover, the left ventricular ejection fraction was determined.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Cell Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Pathology (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention porte sur des méthodes et des dispositifs de diagnostic médical, et spécifiquement, sur une méthode de diagnostic de l'insuffisance cardiaque chez un patient présentant une fibrillation atriale, consistant à déterminer la quantité de GDF-15 dans un échantillon du patient et à la comparer à une quantité de référence ad hoc. L'invention porte également sur un dispositif de diagnostic et sur une trousse d'exécution de ladite méthode.
PCT/EP2008/056261 2007-05-24 2008-05-21 Moyens et méthode de diagnostic de l'insuffisance cardiaque chez un patient atteint d'une fibrillation atriale, à l'aide de gdf-15 et de peptides natriurétiques WO2008142110A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2010508842A JP5015318B2 (ja) 2007-05-24 2008-05-21 Ｇｄｆ−１５及びナトリウム利尿ペプチドを用いた、心房細動を有する患者の心不全を評価するための手段及び方法
US12/621,560 US7955854B2 (en) 2007-05-24 2009-11-19 Assessing heart failure in patients with atrial fibrillation using GDF-15 and natriuretic peptides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP07108852.0 2007-05-24
EP07108852A EP1995596B1 (fr) 2007-05-24 2007-05-24 Procédés d'évaluation de défaillance cardiaque des patients avec une fibrillation auriculaire utilisant des peptides GDF-15

Related Child Applications (1)

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US12/621,560 Continuation US7955854B2 (en) 2007-05-24 2009-11-19 Assessing heart failure in patients with atrial fibrillation using GDF-15 and natriuretic peptides

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WO2008142110A1 true WO2008142110A1 (fr) 2008-11-27

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US (1) US7955854B2 (fr)
EP (1) EP1995596B1 (fr)
JP (1) JP5015318B2 (fr)
AT (1) ATE537454T1 (fr)
ES (1) ES2379104T3 (fr)
WO (1) WO2008142110A1 (fr)

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EP2227696A1 (fr) * 2008-01-08 2010-09-15 Roche Diagnostics GmbH Moyens et procédés pour évaluer le risque de patients se présentant à des unités d'urgence sur la base de gdf-15
ES2512018T3 (es) 2009-07-27 2014-10-23 F. Hoffmann-La Roche Ag Utilización de mimecán en la evaluación de la insuficiencia cardiaca
EP2439535A1 (fr) * 2010-10-07 2012-04-11 F. Hoffmann-La Roche AG Diagnostic de maladies cardiaques liées au diabète et GDF-15 et troponine en tant que prédicteurs pour le développement du diabète sucré de type 2
KR101230088B1 (ko) 2010-11-24 2013-02-05 연세대학교 산학협력단 심방세동의 예후 예측 방법
US20170100460A1 (en) * 2014-06-13 2017-04-13 Novartis Ag Use of serelaxin to reduce gdf-15
CN108700573B (zh) 2016-02-29 2021-06-11 公立大学法人横滨市立大学 检测去势抵抗性前列腺癌的方法和检测试剂
WO2017216387A1 (fr) * 2016-06-17 2017-12-21 Roche Diagnostics Gmbh Angiopoïétine 2 (ang-2) circulante pour la prédiction de récurrence de fibrillation auriculaire
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JP7127422B2 (ja) 2017-08-30 2022-08-30 東ソー株式会社 癌を検出する方法及び検出試薬
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013508708A (ja) * 2009-10-21 2013-03-07 プロノタ エヌ．ヴェ． 体液ホメオスタシスのバイオマーカーとしてのｍｃａｍ
JP2013508707A (ja) * 2009-10-21 2013-03-07 プロノタ エヌ．ヴェ． 急性心不全の診断、予知及び／又は予後用バイオマーカー及びその使用

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ES2379104T3 (es) 2012-04-20
JP2010528275A (ja) 2010-08-19
EP1995596B1 (fr) 2011-12-14
US20100159608A1 (en) 2010-06-24
ATE537454T1 (de) 2011-12-15
JP5015318B2 (ja) 2012-08-29
EP1995596A1 (fr) 2008-11-26
US7955854B2 (en) 2011-06-07

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